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Phase II Clinical, Biological and Pharmacological Study of Rapamycin (Rapamune®, Sirolimus) in Patients With Advanced Pancreatic Cancer

Phase 2
18 Years
Not Enrolling
Pancreatic Cancer

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Trial Information

Phase II Clinical, Biological and Pharmacological Study of Rapamycin (Rapamune®, Sirolimus) in Patients With Advanced Pancreatic Cancer



- To determine the proportion of patients with previously treated advanced pancreatic
cancer surviving at 6 months after treatment with single agent rapamycin.

- To evaluate the relationship between activation of the PI3/Akt/mTOR/S6K signaling
pathway in tumor tissues and rapamycin activity in this patient population.

- To characterize toxicity of rapamycin in this patient population.


- To determine the response rate, median time to treatment failure, and median survival
of patients with previously treated advanced pancreatic cancer who are treated with
single agent rapamycin.

- To characterize the pharmacokinetics of rapamycin in this patient population.

- To explore pharmacogenomic variables that affect rapamycin pharmacokinetics and
clinical activity in this patient population.

- To determine the pharmacodynamic effects of rapamycin on S6 kinase activation in PBMC,
normal skin, and normal oral mucosa obtained from patients treated with the drug and
its relationship with rapamycin pharmacokinetics and clinical effects.

- To explore biomarkers in tumor tissues that might be associated with rapamycin clinical

OUTLINE: Patients receive oral sirolimus once daily on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood, normal skin, and tumor tissue collection at baseline and
periodically during study for pharmacological, biological, and genotyping studies. Blood
samples are analyzed by LC/MS/MS assay to assess rapamycin pharmacokinetics (PKs) during
courses 1 and 2 and to determine baseline CYP3A4 activity. Samples are also analyzed by
genotyping studies to assess CYP3A4 polymorphisms. Pharmacodynamic activity of rapamycin is
assessed in peripheral blood mononuclear cells isolated from PK blood samples using a kinase
assay to measure S6K activity. Tumor tissue is collected from pretreatment tumor samples
obtained at the time of diagnosis or surgery or by biopsy from patients for whom pre-study
tumor specimens are not available. Patients undergo skin biopsies at baseline and on day 1
of course 2 to obtain samples of normal skin. Patients also undergo oral mucosa smears at
baseline and weekly during course 1. Tumor tissue, normal skin, and oral mucosa samples are
assessed by IHC staining of S6K and p-S6K and by RT-PCR for cyclin D1 and p27.

Inclusion Criteria


Inclusion criteria:

- Histologically proven adenocarcinoma of the pancreas

- Locally-advanced or advanced disease which has progressed after one prior
gemcitabine-containing regimen

- Unidimensionally measurable disease (defined as at least one unidimensionally
measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan) OR
evaluable disease

- Tumor tissue available for IHC assessment OR willingness to undergo a safe biopsy of
tumor tissue

Exclusion criteria:

- Histologic or cytologic diagnosis that is not consistent with adenocarcinoma,
including adenosquamous, islet cell, cystadenoma or cystadenocarcinoma, carcinoid, or
small or large cell carcinoma or lymphoma

- Adenocarcinoma arising from a site other than the pancreas (e.g., distal common bile
duct, ampulla of vater or periampullary duodenum)

- Known brain metastases


Inclusion criteria:

- ECOG performance status 0-1

- WBC > 3,500 cells/mm³

- ANC > 1,500 cells/mm³

- Hemoglobin > 9 g/dL

- Serum creatinine ≤ 2.0 mg/dL

- Bilirubin ≤ 2 mg/dL

- ALT, AST, and alkaline phosphatase ≤ 5 times upper limit of normal

- Triglycerides and total cholesterol < 2 times upper limit of normal

- Not pregnant or nursing

Exclusion criteria:

- Uncontrolled medical conditions that could potentially increase the risk of
toxicities or complications of this therapy, including immunodeficiency and chronic
treatment with immunosuppressors

- Gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption, or
active peptic ulcer disease

- Active infections

- History of concurrent malignancy or history of a second malignancy within the past 5

- Clinically significant cardiovascular disease, including myocardial infarction
(within 12 months prior to randomization), unstable angina, grade II or greater
peripheral vascular disease, uncontrolled congestive heart failure, or uncontrolled
hypertension (i.e., systolic blood pressure (BP) > 170 mm Hg, diastolic BP > 95 mm


Exclusion criteria:

- Any unresolved chronic toxicity greater than CTCAE grade 2 from previous anticancer

- Any previous surgery, excluding minor procedures (e.g., dental work or skin biopsy)
within 4 weeks of enrollment

- Participation in an investigational new drug trial within 1 month of starting trial

- Treatment with chemotherapy within 30 days of day 1 treatment

- At least 10 days since prior and no concurrent:

- Cyclosporine

- Diltiazem

- Ketoconazole

- Rifampin

- St. Johns wort

- Grapefruit juice

- Concurrent phenytoin, carbamazepine, barbiturates, or phenobarbital

- No other concurrent investigational or commercial agents

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Proportion of patients surviving after 6 months

Safety Issue:


Principal Investigator

Manuel Hidalgo, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:

JHOC-J0415, CDR0000549899



Start Date:

January 2005

Completion Date:

Related Keywords:

  • Pancreatic Cancer
  • recurrent pancreatic cancer
  • stage III pancreatic cancer
  • stage IV pancreatic cancer
  • adenocarcinoma of the pancreas
  • Pancreatic Neoplasms



Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland  21231-2410